[unreadable] Lung cancer is the leading cause of cancer-related deaths, surpassing the sum total of the next 4 leading cancers while maintaining almost a comparable incidence rate. Cigarette smoking accounts for nearly 90% of all lung cancers, yet only a fraction of smokers develop lung cancer. HOX genes have long been known to act as "master regulators" of embryonic patterning. HOXC6 is expressed in the lung during embryonic patterning and becomes transcriptionally quiescent in the adult lung, a state that is likely to be maintained via a mechanism of active repression. During carcinogenesis, HOXC6 is among the most often reactivated and highly transcribed HOX genes. Dramatic upregulation of HOXC6 protein occurs in 75% of lung squamous cell carcinomas and adenocarcinomas compared to adjacent normal tissues. HOX genes, including HOXC6, also have been implicated as mediators of retinoid signaling, ras-induced carcinogenesis and c-Neu-induced breast carcinogenesis. We hypothesize that HOXC6 plays an important role in lung carcinogenesis via modulation of cellular growth and morphogenesis. This hypothesis will be tested by SAI: To determine if chemical carcinogens of the lung activate HOXC6 expression. Candidate chemical carcinogens will be tested for their ability to activate HOXC6 expression in vitro using mouse primary tracheal and lung epithelial cells. SA2: To determine if HOXC6 modulates chemical carcinogenesis of the lung. Cellular transformation phenotypes will be compared in wild type, HOX6 null, and HOXC6 overexpressor primary cells using conditions optimized in SAI. The main goals of this study are to 1) elucidate the functional significance of HOXC6 and other HOX genes in lung carcinogenesis, 2) understand the molecular mechanisms of chemical carcinogenesis in the lung and 3) validate that HOXC6 can be used as a surrogate to identify novel chemopreventive agents (SA2 system). Applications of these studies may include the development of diagnostics for early detection and patient stratification and novel HOX-associated chemopreventive agents. [unreadable] [unreadable]